1. Field
The present invention relates to novel carbacephem β-lactam antibiotics, and the use of such compounds to treat bacterial infections, in particular, infections caused by bacterial species resistant to conventional β-lactams.
2. Description of the Related Art
Over the past three decades a variety of antibiotics have become available for clinical use. One class of antibiotics that has seen remarkable growth is the β-lactams, over 70 of which have entered clinical use since 1965. Unfortunately, the widespread use of these antibiotics has resulted in an alarming increase in the number of resistant strains, especially among clinically important bacteria such as the genera Salmonella, Enterobacteriaceae, Pseudomonas and Staphylococcus. 
Bacterial resistance to cephalosporins occurs primarily through three mechanisms: (a) destruction of the antibiotic by β-lactamases; (b) decreased penetration due to changes in bacterial outer membrane composition; and (c) alteration of penicillin-binding proteins (PBPs) resulting in interference with β-lactam binding. The latter pathway is especially important, as the binding of β-lactams to PBPs is essential for inhibiting peptidoglycan biosynthesis (peptidoglycan is a required bacterial cell-wall component). Certain Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (“MRSA”) and various genus Enterococcus bacteria are highly resistant to β-lactam antibiotics. The resistance of MRSA is due to the presence of a PBP called PBP2a, which binds very poorly to β-lactam antibiotics. The options for treating infections caused by MRSA are limited and there is a need for new antibiotics with activity against these strains.
In recent years, a novel family of β-lactam antibiotics, the carbacephems (1), has been sporadically touted as having promise against MRSAs and other resistant species. In compound (1), R1 and R2 are generally described as aromatic and heteroaromatic entities, and R3 has generally been reported as an optionally substituted alkyl group.

However, one problem with the carbacephem compounds developed thus far is that researchers investigating the family have been unable to achieve an acceptable balance between MRSA potency and serum protein binding. That is, MRSA activity was demonstrated relatively early on to correlate with lipophilicity; the more lipophilic the carbacephem, the greater its potency. Unfortunately, the greater the lipophilicity of the compound, the greater is its tendency toward high protein binding. Protein binding reduces the concentration of free drug circulating in blood. Lower circulating free drug concentrations typically result in less efficacious beta-lactams. Lack of oral bioavailability is another issue facing MRSA active beta-lactams. Historically, cephalosporins were both poorly absorbed by oral dosing and suffered from hydrolytic degradation, due to chemical instability, in the acidic environment of the stomach. Carbacephems offer an advantage for treating community-acquired MRSA which is most conveniently treated by oral antibiotics. Since carbacephems, due to their molecular structure, are intrinsically more stable to the gastric environment, this class of beta-lactam has a much greater potential for development as an oral agent.
Despite the above, carbacephems remain an intriguing approach to dealing with MRSA and other resistant bacterial species. What is needed, however, is a novel class of carbacephems that achieves the requisite balance of MRSA potency, protein binding and oral availability. The present invention addresses this need and provides further related advantages.